My long-term goals are to understand the molecular mechanisms of human hereditary tumor syndromes. Multiple endocrine neoplasia type I (MEN1) is a dominantly inherited disease characterized by development of tumors in multiple endocrine organs. The tumors from the pancreatic islets and intestines have a high malignant potential. The gene mutated in MEN1 patients, tumor suppressor gene menin, has been cloned, but its function in suppressing tumorigenesis is unclear. Thus, a key question is what is the function of menin in suppressing tumorigenesis in MEN1 ? This proposal seeks to address such a question, and it is largely based on our recent findings: (1) Menin associates with chromatin and nuclear matrix; (2) Menin interacts with FANCD2, a gene involved in DNA repair, and the menin -/-cells are hypersensitive to DNA damage; (3) Menin induces a Bax/Bak-dependent apoptotic pathway. We hypothesize that menin regulates gene transcription by associating with chromatin and nuclear matrix, participates in DNA repair in concert with FANCD2, and control a DNA damage-induced apoptotic pathway. Thus, the goals of this proposal are to characterize the roles of menin in regulating gene transcription, DNA repair, and apoptosis. To test these hypotheses, first, we will identify domains of menin that mediate association with chromatin or the nuclear matrix and analyze their role in regulation of gene transcription. Second, we will characterize the roles of menin in DNA repair in concert with FANCD2 in cultured ceils and in a mouse model. Third, the relevance of menin-mediated apoptosis to MEN1 and menin-regulated steps of apoptosis will be investigated. Information generated from these independent yet complementary studies will likely significantly advance our understanding of the molecular pathogenesis of MEN 1 and shed lights on improving therapeutic interventions for MEN1.